Hypoxia‐Induced O‐GlcNAcylation of GATA3 Leads to Excessive Testosterone Production in Preeclamptic Placentas

The maintenance of endocrine homeostasis in the placenta is crucial for ensuring successful pregnancy. An abnormally elevated production of placental testosterone (T₀) has been documented in patients with early-onset preeclamptic (E-PE). However, the underlying mechanisms remain unclear. In this study, we found that E-PE placentas exhibited significantly increased expressions of 3β-HSD1 (3β-Hydroxysteroid Dehydrogenase 1) and 17β-HSD3 (17β-Hydroxysteroid Dehydrogenase 3), the rate-limiting enzymes for T₀ synthesis. This was strongly correlated with an elevated level of O-linked N-acetylglucosaminylation (O-GlcNAcylation) of GATA3 (GATA binding protein 3). In human trophoblast cells, O-linked-N-acetylglucosamine (O-GlcNAc) modification of GATA3 on Thr³²² stabilized the protein and enhanced the transcriptional regulation of 3β-HSD1 and 17β-HSD3, thereby increasing T₀ production. Hypoxia, a well-established pathological factor in PE, significantly enhanced the O-GlcNAcylation of GATA3 in human trophoblast cells. Our findings suggest that hypoxia-induced overactive O-GlcNAcylation of GATA3 contributes to the exacerbated T₀ production in E-PE placentas. These findings provide a new perspective on the pathogenesis of E-PE from the standpoint of posttranslational regulation and may illuminate novel therapeutic strategies for adverse pregnancy outcomes such as E-PE.